Dr. Daniel Acosta and In Vitro toxicology at the U.S. Food and Drug Administration's National Center for Toxicological Research.

For the past five years, Dr. Daniel Acosta has served as the Deputy Director of Research at the National Center for Toxicological Research (NCTR), a principle research laboratory of the U.S. Food and Drug Administration (FDA). Over his career at NCTR, Dr. Acosta has had a major impact on developing and promoting the use of in vitro assays in regulatory toxicity and product safety assessments. As Dr. Acosta nears his retirement we have dedicated this paper to his many accomplishments at the NCTR. Described within this paper are some of the in vitro studies that have been conducted under Dr. Acosta's leadership. These studies include toxicological assessments involving developmental effects, and the development and application of in vitro reproductive, heart, liver, neurological and airway cell and tissue models.

Pig-a gene mutation database.

Mutations in the X-linked phosphatidylinositol glycan, class A gene (Pig-a) lead to loss of glycosylphosphatidylinositol (GPI) anchors and GPI-anchored proteins from the surface of erythrocytes and other mammalian cells. The Pig-a gene mutation assay quantifies in vivo gene mutation by immunofluorescent labeling and flow cytometry to detect the loss of GPI-anchored proteins on peripheral blood erythrocytes. As part of the regulatory acceptance of the assay, a public database has been created that provides detailed information on Pig-a gene mutation assays conducted in rats and mice. A searchable version of the database is available through a website designed and hosted by the University of Maryland School of Pharmacy. Currently, the database contains only mouse and rat data, but it is anticipated that it will expand to include data from other species, including humans. A major purpose in developing the database was to aid in the preparation of a Retrospective Performance Analysis and Detailed Review Paper required for Organisation for Economic Co-operation and Development Test Guideline acceptance. We anticipate, however, that it also will be useful for accessing and comparing Pig-a data to data from other assays and for conducting quantitative assessments of Pig-a gene mutation responses. Environ. Mol. Mutagen., 60:759-762, 2019. © 2019 Wiley Periodicals, Inc.

Evaluating Mode of Action of Acrolein Toxicity in an In Vitro Human Airway Tissue Model.

Acrolein is a reactive unsaturated aldehyde and is found at high concentrations in both mainstream and side-stream tobacco smoke. Exposure to acrolein via cigarette smoking has been associated with acute lung injury, chronic obstructive pulmonary diseases (COPDs), and asthma. In this study, we developed an in vitro treatment strategy that resembles the inhalation exposure to acrolein experienced by smokers and systematically examined the adverse respiratory effects induced by the noncytotoxic doses of acrolein in a human airway epithelial tissue model. A single 10-min exposure to buffered saline containing acrolein significantly induced oxidative stress and inflammatory responses, with changes in protein oxidation and GSH depletion occurring immediately after the treatment whereas responses in inflammation requiring a manifestation time of at least 24 h. Repeated exposure to acrolein for 10 consecutive days resulted in structural and functional changes that recapitulate the pathological lesions of COPD, including alterations in the beating frequency and structures of ciliated cells, inhibition of mucin expression and secretion apparatus, and development of squamous differentiation. Although some of the early responses caused by acrolein exposure were reversible after a 10-day recovery, perturbations in the functions and structures of the air-liquid-interface (ALI) cultures, such as mucin production, cilia structures, and morphological changes, failed to fully recover over the observation period. Taken together, these findings are consistent with its mode of action that oxidative stress and inflammation have fundamental roles in acrolein-induced tissue remodeling. Furthermore, these data demonstrate the usefulness of analytical methods and testing strategy for recapitulating the key events in acrolein toxicity using an in vitro model.